This NIMH Mentored Patient-Oriented Career Development (K23) award application is to support Dr. Michael Cerullo's long-term career objective of developing an expertise in the neurophysiology of depression in bipolar disorder (BPD) using innovative neuroimaging techniques. Little research has focused specifically on understanding the neurophysiology of depression associated with BPD, yet patients spend considerably more time in depressive rather than manic episodes and suffer more morbidity during depression. In order to achieve his career goals and advance our understanding of bipolar depression, the candidate proposes to gain expertise in functional MRI (fMRI), the neurophysiology of mood disorders, neuropsychology, statistical analysis, and the ethical conduct of research by participating in course work, didactic readings, mentoring, and the proposed research activities. By using fMRI and directly contrasting patients with major depressive disorder (MDD) and BPD during depression, it is possible to identify core brain regions involved in BPD. Only one prior fMRI study has directly compared BPD and MDD patients during depression, but was limited by the use of an exclusively emotional task. Bipolar patients, even while euthymic, also suffer cognitive deficits. The cognitive and mood symptoms of depression are generated by different but reciprocally connected brain networks and their interactions. Tasks that are purely emotional or cognitive may not permit examination of this interaction and may therefore be unable to elucidate brain abnormalities underlying mood dysregulation in BPD. Therefore we propose to use fMRI to compare regional brain activation between bipolar and unipolar depressed patients using a task designed to evaluate both the emotional and cognitive networks and their intersection. Prior neuroimaging research studies support the importance of the cerebellar vermis and striatum in BPD. We hypothesize that dysfunction in these two brain regions contributes to the breakdown in the regulation of the prefrontal-striatal-thalamic circuits that maintain emotional homeostasis. The proposed integrated research and training programs, together with the productive research environments of the Division of Bipolar Disorders Research and the Center for Imaging Research at the University of Cincinnati, will foster the candidate's development into an independent investigator in mood disorders. The research conducted will advance our understanding of the neurophysiology of depression in BPD.